Male to female ratio in autism - the role of steroids and calcium
signalling

Autism affects more boys than girls, the overall male to female
in autism being 4:1. One possible explanation for this difference
in prevalence is the role of androgens. For example, it has been
suggested that prenatal exposure to high levels of testosterone
influences some autistic traits and makes fetuses more susceptible
to developing autism [16624315].
Testosterone is a steroid hormone from the androgen group. It
is derived from cholesterol, with largest amounts being produced
by the Leydig cells in the testes in men, and some being produced
by the adrenal glands, ovaries and in the placenta. Estrogens
function as the primary female sex hormone and are present at
significantly higher levels in women. Estradiol 17beta is one
of the major naturally occurring estrogens.

A growing number of studies in recent years have shed light on
the mechanisms behind the effect of testosterone
on gender-related differences in cardiac preformance. It has been
observed that testosterone induces an increase in calcium by increasing
expression and activity of LTCC in coronary arteries, in particular
the expression of Cav1.2 [9166901,
16243844,
15114516,
15242831].
Testosterone-induced increases in calcium levels appear to be
G-protein linked and sensitive to Pertussis toxin treatment, and
involve emptying of intracellular calcium stores downstream from
LTCC activation [16339199].
Testosterone potentiation of calcium channels has also been observed
in several other cells [8969193,
1883394].

On the other hand an increasing line of evidence indicates that
estrogen acts as both cardioprotective as well
as neuroprotective agent, primarily by inhibiting LTCC
and rises in intercellular calcium levels [17082253].
Estradiol is thought to influence various brain functions by acting
on receptors on the neuronal membrane surface. Many intracellular
signaling pathways and modulatory proteins are affected by estradiol
via this mechanism, including regulation of CREB, a stimulus-induced
transcription factor that regulates various behaviors, including
those related to addiction and chronic pain, as well as neuronal
survival, proliferation, and differentiation (see Brain).
One study has shown that estradiol attenuats CREB phosphorylation
mediated by calcium influx through LTCC [15901789].
Administration of nifedipine, a calcium antagonist, mimicks the
effects of estrogen on the peripheral nervous system [12732239].
Both nifedipine and estrogen protected neurons from amyloid-protein-induced
toxicity through supression of calcium channel protein expression
induced by this protein [15082219].
17beta-estradiol was also able to attenuate glutamate-induced
calcium overload in rat primary hippocampal neurons [15488487].
(see Hypoxia/Ischemia re protective
effects of estrogen on brain arteries).

In addition, estrogen has been reported to have anti-oxidant properties
- anti-oxidant effects of estrogen reduce intracellular calcium
during metabolic inhibition and protect against damaging effect
of calcium loading on mitochondria [12676548,
15723615]
(see Mitochondria).

In terms of testosterone synthesis and secretion,
calcium is an important modulator of Leydig cell steroidogenesis,
which is mainly controlled by luteinizing hormone secreted from
the anterior pituitary. Testosterone production in response to
lutenising hormone is shown to be lower in the absence of extracellular
calcium and in the presence of verapamil, a calcium channel blocking
agent [9695359].

Testosterone formation in response to both lactate and to 4 beta-Phorbol-12-myristate-13-acetate
(PMA) also appears to be dependent on extracellular calcium and
could be blocked in vitro by the addition of the calcium channel
blocking agents [2988910,
11500963].